One other thing I wanted to mention about the PLUTO trial is the entry criterion. The main entry criterion was the presence of clear lower urinary tract obstruction in a male fetus, if ‘the clinician was uncertain as to the optimum management.’

Now I understand the reason for that, but in fact, as I have been mentioning in many of my previous posts about SUPPORT’ it is implicit in the ethical principles guiding all trials. If the clinician is certain as to the optimum management, and one arm of the trial requires withholding that optimal management, then it would be morally indefensible to enroll a patient in that trial. The problem with using that as the main entry criterion, without other severity of illness criteria, is that it then become very difficult to extrapolate the results to other populations.

It really reminds me of the INNOVO trial. For that trial of rescue inhaled NO therapy in the preterm infant the main entry criterion was that ‘Infants of <34 weeks’ gestation, aged <28 days, and with severe respiratory failure requiring ventilatory support (and having had surfactant when appropriate) were eligible for trial entry if the responsible clinician was uncertain about whether an infant might benefit from iNO.’

That is ethically entirely defensible, but, I don’t know the varieties of opinion among neonatologists in the UK, and who they might feel would definitely benefit, or definitely not benefit from iNO. I do know that they randomized a desperately sick group of babies: the average OI at baseline was 32, which for a premie is really, really bad; and the mortality was about 60% (it wasn’t affected by NO by the way), proving that an OI of 32 in a premie is really, really, bad.

So the quality of the trial was very high, but how do we determine the external applicability? I now know that a premie in my NICU who is very sick and for whom an average neonatologist in the UK would not be sure about whether iNO was indicated, would probably not benefit from iNO. I actually have lots of other data about rescue iNO in the preterm, but if this was the main source of data I would find it very hard to know how to apply these results.

Now perhaps you could say that I don’t know much about the non-enrolled subjects in other trials either, which is true, and is a good reason for trying to collect as much data as we are allowed to on non-enrolled eligible subjects; but that will be tough to do unless we have objective eligibility criteria, to know who could qualify to be a subject, and what happened to them if they were not enrolled. That is one of the great benefits of the CONSORT approach, and why we should insist of having all of the CONSORT flow diagram data in reports of RCTs.

I also don’t know, in the specific instance of the INNOVO trial, how a caregiver could possibly have been certain, before doing the trial, whether or not a baby would benefit from iNO. Before INNOVO there was little data, mostly from very small trials, and absolutely no certainty at all about the role of iNO in rescue treatment of sick preterm babies. That is why I think it is preferable in such a circumstance to say, ‘we do not know if any preterm baby with an OI over 15 despite surfactant benefits from iNO, they will therefore all be eligible for randomization’ but with the understanding that if there is some specific circumstance which makes iNO either clearly indicated or clearly contra-indicated, under such a circumstance it is inappropriate to randomize the baby, and we should seek consent to collect data.

Incidentally the PLUTO group are collecting a lot of information about interventions and outcomes of other mothers/fetal pairs with the diagnosis in the participating centers, which will help to make it clear how representative the PLUTO results are in comparison with non- randomized patients.